Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV

ABSTRACT

Ivabradine hydrochloride Form IV, its pharmaceutical composition, process for its preparation, and its use as therapeutically active ingredient and pharmaceutical compositions containing Ivabradine hydrochloride Form IV.

FIELD OF THE INVENTION

The present invention relates to ivabradine hydrochloride Form IV, aprocess for its preparation, its use as therapeutically activeingredient, and pharmaceutical compositions containing it.

BACKGROUND OF THE INVENTION

Ivabradine,(+)-3-[3-[N-[4,5-Dimethoxybenzocyclobutan-1(S)-ylmethyl]-N-methylamino]propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one,is represented by the structural formula (I):

Ivabradine, and addition salts thereof with a pharmaceuticallyacceptable acid, and more especially its hydrochloride, have veryvaluable pharmacological and therapeutic properties, especiallybradycardic properties, making those compounds useful in the treatmentor prevention of various clinical situations of myocardial ischaemiasuch as angina pectoris, myocardial infarct and associated rhythmdisturbances, and also in various pathologies involving rhythmdisturbances, especially supraventricular rhythm disturbances, and inheart failure.

Ivabradine is currently marketed with trade name Corlentore andProcolarane for treatment of chronic stable angina pectoris in coronaryartery disease patients with normal sinus rhythm.

The preparation and the therapeutic use of ivabradine and addition saltsthereof with a pharmaceutically acceptable acid, and more especially itshydrochloride, have been described in the European patent specificationEP0534859.

EP0534859 describes a synthesis process for ivabradine and itshydrochloride salt. It is disclosed a product recrystallized inacetonitrile with its melting point Mp: 135-140° C.

EP1589005 discloses the crystalline Form α of ivabradine hydrochloride,characterized by PXRD, and a process for its preparation.

EP1695965 discloses the crystalline Form β, a tetrahydrate form ofivabradine hydrochloride, characterized by PXRD, and a process for itspreparation.

EP1695710 discloses the crystalline Form βd of ivabradine hydrochloride,characterized by PXRD, and a process for its preparation.

EP1707562 discloses the crystalline Form γ, a monohydrate form ofivabradine hydrochloride, characterized by PXRD, and a process for itspreparation.

EP1695709 discloses the crystalline Form γd of ivabradine hydrochloride,characterized by PXRD, and a process for its preparation.

EP1775288 discloses the crystalline Form δ, a hydrated form ofivabradine hydrochloride, characterized by PXRD, and a process for itspreparation.

EP1775287 discloses the crystalline Form δd of ivabradine hydrochloride,characterized by PXRD, and a process for its preparation.

WO2008/125006 discloses a crystalline form of ivabradine hydrochloride,characterized by PXRD, and a process for its preparation.

CN101768117 discloses a crystalline form of ivabradine hydrochloride,characterized by PXRD, and a process for its preparation.

CN101805289 discloses the crystalline Form ω of ivabradinehydrochloride, characterized by PXRD, and a process for its preparation.

WO2011/098582 discloses three crystalline forms of ivabradinehydrochloride, characterized by PXRD, and a process for its preparation.

WO2008/146308, CN101463008, CN101597261 and CN102050784 discloseamorphous form of ivabradine hydrochloride and a process for itspreparation.

The polymorphic behaviour of drugs can be of crucial importance inpharmacy and pharmacology. Polymorphism is the ability of a substance tocrystallize in different crystal modifications, each of them having thesame chemical structure but different arrangements or conformations ofthe molecules in the crystal lattice. The differences in physicalproperties exhibited by polymorphs affect pharmaceutical parameters suchas storage stability, compressibility and density (important informulation and product manufacturing), and dissolution rates (animportant factor in determining bio-availability). Differences instability can result from changes in chemical reactivity or mechanicalchanges or both. For example, a dosage form originating from onepolymorph might discolor more rapidly when compound to another from adifferent polymorph. Or tablets might crumble on storage as akinetically favoured polymorph spontaneously converts into athermodynamically more stable polymorphic form. As a result ofsolubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of the crystalmay be important in processing: for example, one polymorph might be morelikely to form solvates or might be difficult to filter and wash free ofimpurities.

The most important solid state property of a pharmaceutical substance isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's gastric fluid may have therapeuticconsequences as it imposes an upper limit on the rate at which anorally-administered active ingredient reaches the blood stream. Thesolid state polymorphic form of a compound may also affect its behaviouron compaction and its storage stability.

These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. The polymorphicform may give rise to thermal behaviour different form that of theamorphous material (or) another polymorphic form.

The discovery of new polymorphic forms of a pharmaceutically usefulcompound provides a new opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has for designing, forexample, a pharmaceutical dosage form of a drug with a targeted releaseprofile or other desired characteristic.

Usually the most stable polymorphic form is preferred in a marketedformulation, because any other polymorphs are metastable and maytherefore transform to the more stable form. Overlooking the most stablepolymorph may cause failure of a marketed product due to phasetransformation during storage. A late-appearing stable polymorph canhave a great impact on development timelines. Although metastable formsmay survive years if a considerable activation energy barrier has to beovercome in moving from the metastable state to the stable state, thisactivation-energy barrier may be reduced by moisture, catalysts,impurities, excipients or temperature and the transformation into thestable form occurs spontaneously. Seeds of the stable form may alsoaccelerate transformations. Therefore using a thermodynamically unstablemodification in the production of tablets is sometimes the reason whyunwanted changes take place in such formulations after a time ofstorage. Therefore, there is a need for a thermodynamically stablepolymorphic form of ivabradine hydrochloride and methods of itspreparation.

A method described by Haleblian and McCrone can be used to determine themost stable polymorph at room temperature. This method utilizes the factthat the most stable polymorph will also be the less soluble at a giventemperature and pressure. If crystals of both polymorphs are present ina saturated solution, the most stable form will grow at the expense ofthe less stable one. This method is called the solution phasetransformation or solvent mediated transformation.

Therefore, there is a demand for alternative pure and crystalline formsof ivabradine hydrochloride which would be suitable for use in thepharmaceutical industry and, in particular, allow easy production ofivabradine preparations in solid form meeting strict pharmaceuticalstandards, such as tablets, capsules, chewable tablets, powders, etc.for oral administration.

To prepare pharmaceutical compositions containing ivabradinehydrochloride Form IV for administration to mammals in accordance withexacting health registration requirements of the U.S. and internationalhealth registration authorities, e.g. the FDA's Good ManufacturingPractices (“GMP”) requirements, there is a need to produce ivabradinehydrochloride Form IV in as pure a form as possible, especially a formhaving constant physical properties.

SUMMARY OF THE INVENTION

The applicants have now discovered that the drug substance ivabradinehydrochloride exists in a thermodynamically stable polymorphic formunder certain experimental conditions of isolation or purification(ivabradine hydrochloride Form IV). This crystalline form is stable andeasy to handle. The improved physical characteristics of said stablecrystalline form compared with the ivabradine hydrochloride described inthe art, involve enhanced manufacturing capabilities and the provisionof a compound suitable for use in the preparation of pharmaceuticalformulations.

The applicants have discovered that ivabradine hydrochloride exists as aless thermodynamically stable polymorph or a mixture of polymorphs. Sucha mixture could lead to production of a ivabradine hydrochloride Form IVproduct which would exist as a variable mixture of variable composition(i.e., variable percent amounts of polymorphs) having variable physicalproperties, a situation unacceptable in view of stringent GMPrequirements.

The applicants surprisingly and unexpectedly have obtained a novelthermodynamically stable and pure crystalline form of ivabradinehydrochloride (ivabradine hydrochloride Form IV), having constantphysical properties.

Ivabradine hydrochloride Form IV of the present invention is obtainedwith high yields and elevated richness. Furthermore, the dryingconditions used do not affect in the stability of the process, itspreparation process is consistently reproducible and robust, and,therefore, easily industrializable. In addition, solvents used duringprocess of obtainment, such as toluene, can be removed without observingchanges in the resulting crystalline form (Form IV) or other properties.

Moreover, the applicants have discovered that ivabradine hydrochlorideForm IV shows a suitable dissolution profile. The ivabradinehydrochloride Form IV is particularly suitable to obtain immediaterelease tablets. These tablets can be prepared by known and conventionalprocesses, including direct compression, dry granulation and/or wetgranulation. The wet granulation process is performed using organicsolvents, acetone or alcohols (such as ethanol, methanol andisopropylalcohol), or the combination thereof.

Furthermore, these tablets can be coated by different conventionalexcipients. The commonly used coating agents are derivatives ofcellulose such as hydroxypropylmethylcellulose (HPMC) andhydroxypropylcellulose (HPC), derivatives of Poly(methyl methacrylate)(PMMA) such as Eudragit®, Polyvinyl alcohol (PVA) and derivates ofPolyvinyl alcohol.

Thus, one aspect of the present invention relates to ivabradinehydrochloride Form IV.

In another embodiment, the invention relates to ivabradine hydrochlorideForm IV as defined above, with a powder X-ray diffraction comprising thefollowing 2 theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29,wherein the X-ray diffraction is measured using a CuKα radiation.

In another embodiment, the invention relates to ivabradine hydrochlorideForm IV as defined above, with a powder X-ray diffraction comprising thefollowing 2 theta (±0.2) peaks: 8.11, 8.74, 15.55, 17.17, 19.18, 19.89,21.82, 22.49, 24.29 and 24.53, wherein the X-ray diffraction is measuredusing a CuKα radiation.

In another embodiment, the invention relates to ivabradine hydrochlorideForm IV as defined above, with a powder X-ray diffraction essentially asdepicted in FIG. 1.

In another embodiment, the invention relates to ivabradine hydrochlorideForm IV as defined above, having a Differential Scanning calorimetrythermogram which shows one endothermic peak from 153° C. to 157° C.

In another embodiment, the invention relates to ivabradine hydrochlorideForm IV as defined above, having a Differential Scanning calorimetrythermogram essentially as depicted in FIG. 2.

In another embodiment, the invention relates to ivabradine hydrochlorideForm IV as defined above, with an average particle size from 0.1 to 600μm, preferably from 10 to 100 μm, determined by laser diffraction usingMalvern Mastersizer 2000 laser diffraction instrument.

Another aspect of the present invention relates to ivabradinehydrochloric Form, which is essentially the crystalline form disclosedabove.

Another aspect of the present invention relates to a process forpreparing ivabradine hydrochloride Form IV as defined above, whichcomprises the step of:

a) slurrying ivabradine hydrochloride in a solvent system, wherein thesolvent system comprises toluene, ethanol, acetone, methyl ethyl ketone,methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixturesthereof.

In another embodiment, the invention relates to the process as definedabove, wherein the solvent system comprises at least two solvents.

In another embodiment, the invention relates to the process as definedabove, wherein the solvent system comprises toluene and a second solventselected from ethanol, acetone and ethyl acetate.

In another embodiment, the invention relates to the process as definedabove, wherein the temperature of step (a) is lower than 60° C.,preferably between 10° C. and 60° C., preferably is lower than 40° C.,more preferably from 10° C. to 30° C. and even more preferably from 20°C. to 25° C.

In another embodiment, the invention relates to the process as definedabove, wherein the reaction time for performing step (a) is less than 48h, preferably is less than 24 h.

In another embodiment, the invention relates to the process as definedabove, wherein the proportion in step (a) of liter of the solvent systemversus kilogram of ivabradine hydrochloride Form IV is from 5 to 50,preferably from 8 to 12.

In another embodiment, the invention relates to the process as definedabove, wherein the solvent system in step (a) is essentially toluene.

In another embodiment, the invention relates to the process as definedabove, further comprising after performing step (a), the step of:

b) isolating the ivabradine hydrochloride Form IV.

In another embodiment, the invention relates to the process as definedabove, further comprising after performing step b, the step of:

c) drying the isolated ivabradine hydrochloride Form IV under vacuumpressure, preferably at a pressure from 25 mm Hg to, but not including,760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at atemperature between 45° C. and 70° C.

Another aspect of the present invention relates to a process forpreparing ivabradine hydrochloride Form IV as defined above, comprisingthe steps of:

a) slurrying ivabradine hydrochloride in a solvent system, wherein thesolvent system comprises toluene, ethanol, acetone, methyl ethyl ketone,methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixturesthereof;

b) isolating the ivabradine hydrochloride Form IV, and

c) drying the isolated ivabradine hydrochloride Form IV under vacuumpressure, preferably at a pressure from 25 mm Hg to, but not including,760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at atemperature between 45° C. and 70° C.

Another aspect of the present invention relates to a process forpreparing ivabradine hydrochloride Form IV as defined above, comprisingthe steps of:

i) stirring a solution of ivabradine free base in a solvent system,wherein the solvent system comprises toluene, ethanol, acetone, methylethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetateand mixtures thereof;

ii) maintaining the solution at a temperature lower than 60° C.,preferably between 10° C. and 60° C., more preferably lower than 40° C.;and more preferably between 10° C. and 40° C.

iii) adding a solution of hydrochloric acid to obtain ivabradinehydrochloride;

iv) seeding with the ivabradine hydrochloride Form IV;

v) isolating the ivabradine hydrochloride Form IV; and

vi) drying the isolated ivabradine hydrochloride Form IV under vacuumpressure, preferably at a pressure from 25 mm Hg to, but not including,760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at atemperature between 45° C. and 70° C.

In another embodiment, the invention relates to the process as definedabove, wherein the solvent system of step (i), is toluene.

In another embodiment, the invention relates to the process as definedabove, wherein the solution of chlorhydric acid of step (iii), is ahydrochloric acid solution in ethanol.

Another aspect of the present invention relates to a process forpreparing ivabradine hydrochloride Form IV as defined above, comprisingthe steps of:

i′) stirring a solution of ivabradine free base in a solvent system,wherein the solvent system comprises toluene, ethanol, acetone, methylethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetateand mixtures thereof;

ii′) maintaining the solution at a temperature lower than 60° C.,preferably between 10° C. and 60° C., more preferably lower than 40° C.;and more preferably between 10° C. and 40° C.

iii′) seeding with the ivabradine hydrochloride Form IV;

iv′) adding a solution of hydrochloric acid to obtain ivabradinehydrochloride;

v′) isolating the ivabradine hydrochloride Form IV; and

vi′) drying the isolated ivabradine hydrochloride Form IV under vacuumpressure, preferably at a pressure from 25 mm Hg to, but not including,760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at atemperature between 45° C. and 70° C.

In another embodiment, the invention relates to the process as definedabove, wherein the solvent system of step (i′), is toluene.

In another embodiment, the invention relates to the process as definedabove, wherein the solution of chlorhydric acid of step (iv′), is ahydrochloric acid solution in ethanol.

Another aspect of the present invention relates to a pharmaceuticalcomposition comprising ivabradine hydrochloride Form IV as definedabove, and at least a pharmaceutically acceptable excipient.

In another embodiment, the invention relates to the pharmaceuticalcomposition as defined above, for oral administration.

In another embodiment, the invention relates to the pharmaceuticalcomposition as defined above, in the form of tablets.

In another embodiment, the invention relates to the pharmaceuticalcomposition as defined above, in the form of film-coated tablets.

In another embodiment, the invention relates to the coating agents,preferably these agents are derivatives of cellulose, more preferablyhydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC),derivatives of Poly(methyl methacrylate) (PMMA), more preferablyEudragitt®, Polyvinyl alcohol (PVA) and derivates of Polyvinyl alcohol.

In another embodiment, the invention relates to the pharmaceuticalcomposition as defined above that contains 5 to 9 mg of ivabradinehydrochloride Form IV.

In another embodiment, the invention relates to a film-coated tabletcontains about 5 mg ivabradine as free base (equivalent to 5.390 mgivabradine hydrochloride Form IV).

In another embodiment, the invention relates to a film-coated tabletcontains about 7.5 mg ivabradine as free base (equivalent to 8.085 mgivabradine hydrochloride Form IV).

Another aspect of the present invention relates to a process for themanufacture of the pharmaceutical composition as defined above,characterized in that direct compression, dry granulation and/or wetgranulation techniques are used.

Another aspect of the present invention relates to a wet granulationprocess characterized in that said process comprises using organicsolvents, preferably acetone or alcohols (such as ethanol, methanol andisopropylalcohol) or the combination thereof.

Another aspect of the present invention relates to ivabradinehydrochloride Form IV as defined above or the pharmaceutical compositionas defined above, for use in therapy.

Another aspect of the present invention relates to ivabradinehydrochloride Form IV as defined above or the pharmaceutical compositionas defined above, for use in the treatment of bradycardics, myocardialischaemia, supraventricular rhythm disturbances, chronic stable anginapectoris in coronary artery disease adults with normal sinus rhythm,myocardial infarct, heart failure and associated rhythm disturbances.

In the above definitions, the term “under vacuum” refers to conditionswhere the air (gas) pressure surrounding the substrate has been reducedbelow atmospheric pressure. Preferably under vacuum refers to a pressurefrom 25 mm Hg to 760 mm Hg (with the proviso that 760 mm Hg is notincluded), and more preferably from 50 mm Hg to 200 mm Hg.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the invention encompasses a thermodynamically stablepolymorphic form of ivabradine hydrochloride. This Form may becharacterized by X-ray diffraction diagram, measured with a Copper X-raysource, exhibiting characteristic peaks, degrees 2 theta, at about:

Relative Angle [°2theta] Intensity [%] 8.11 11.59 8.74 9.73 15.55 100.0017.17 85.38 19.18 78.06 19.89 54.44 21.82 54.91 22.49 64.80 24.29 53.8424.53 56.00and additionally, by one endothermic peak about 155° C. as measured bydifferential scanning calorimetry (DSC).

The invention also encompasses a process for preparing the claimedcrystalline form of ivabradine hydrochloride which comprises the step ofslurrying ivabradine hydrochloride in a slurry solvent selected fromtoluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone,ethyl acetate, isopropyl acetate and mixtures thereof. Toluene is apreferred slurry solvent and can be used alone or with a second solventselected from ethanol, acetone and ethyl acetate.

The present invention also discloses a process for preparing the claimedcrystalline form of ivabradine hydrochloride which further comprises thestep of drying the isolated ivabradine hydrochloride after the slurryingstep at a pressure less than 760 mm Hg and the temperature is about 65°C.

Processes for preparing the claimed crystalline form of ivabradinehydrochloride disclosed in the present invention, optionally can includethe step of seeding with the novel crystalline form of ivabradinehydrochloride disclosed in the present invention.

Differential scanning calorimetry (DSC) analyses were carried out bymeans of a Mettler-Toledo DSC-822e calorimeter. Experimental conditions;aluminium crucibles of 40 μL volume, atmosphere of dry nitrogen with 50mL/min flow rate, heating rate of 10° C./min. The calorimeter wascalibrated with indium of 99.99% purity. Instrument could result in adifferent thermogram. The present invention is characterized by thethermogram values set forth herein obtained using this DSC Instrument aswell as the equivalent thermogram values obtained using other types ofDSC instruments.

Thermal Gravimetric Analyses (TGA) were performed on a Mettler-ToledoTGA-851e thermobalance. Experimental conditions: alumina crucibles of 70mL volume, atmosphere of dry nitrogen with 50 mL/min flow rate, heatingrate of 10° C./min.

Ivabradine hydrochloride Form IV PXRD analyses: The powder samples weresandwiched between polyester films of 20 micrometers of thickness andanalysed in a PANalytical X'Pert PRO MPD θ/θ powder diffractometer of240 millimeters of radius, in a configuration of convergent beam with alocalizing mirror and a flat sample transmission geometry, in thefollowing experimental conditions: Cu K α radiation (I=1.5418 Ā); Workpower: 45 kV and 40 mA; Incident beam slits defining a beam height of0.4 millimeters; Incident and diffracted beam 0.02 radians Seller slits;PIXcel detector: Active length=3.347 Å°; 2θ/θ scans from 2 to 40°2θ witha step size of 0.026°2θ and a measuring time of 75 seconds per step.

The term “about” when used in the context of the present inventionrefers to ±10% of the specified amount. For the purpose of thisinvention, for X-ray diffraction patterns, depending on the calibration,sample or instrumentation, peaks at 2q can shift up to ±0.2 degrees(error). In one embodiment, all peaks in X-ray diffraction pattern shiftup to +0.2 degrees, or up to −0.2 degrees. An X-ray diffraction patternor peaks within that error is considered the same or substantiallysimilar.

Fourier Transform Infrared—Attenuated Total Reflectance (FT-IR-ATR)spectra were registered on a Perkin Elmer Spectrum One/100 FT-IRspectrometer with universal attenuated total reflectance (ATR) samplingaccessory (SPECTRUM100 with UATR1BOUNCE). Sample is placed on the AIRplate and the measure is carried out in the 650-4000 cm-1 range. Theterm “IR or IR spectrum/spectra” when used in the context refers tospectra registered in the conditions mentioned above.

The term “MiBK” when used in the context of the present invention refersto methyl isobutyl ketone.

The term “MEK” when used in the context of the present invention refersto methyl ethyl ketone.

For the purposes of the invention, any ranges given include both thelower and the upper end-points of the range.

The following drawings and examples illustrate the scope of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: shows a x-ray diffractogram for the novel crystalline form ofivabradine hydrochloride.

FIG. 2: shows a DSC thermogram for the novel crystalline form ofivabradine hydrochloride.

FIG. 3: shows an IR for the novel crystalline form of ivabradinehydrochloride.

FIG. 4: shows a TGA analysis for the novel crystalline form ofivabradine hydrochloride.

EXAMPLES Preparative Example 1 Crystalline Ivabradine Hydrochloride

Crystalline ivabradine hydrochloride was obtained according to theprocess described in the patent EP0534859.

Preparative Example 2 Form α of Ivabradine Hydrochloride

Form α ivabradine hydrochloride was obtained according to the processdescribed in the patent EP1589005.

Preparative Example 3 Form δ of Ivabradine Hydrochloride

Form δ was obtained according to the process described in the patentEP1956005.

Preparative Example 4 Form δd of Ivabradine Hydrochloride

Form δd was obtained according to the process described in the patentEP1775287.

Preparative Example 5 Ivabradine

Ivabradine was obtained according to the process described in the patentEP0534859.

Example 1 Form IV of Ivabradine Hydrochloride

15.0 g of crystalline ivabradine hydrochloride of preparative Example 1with a Karl Fisher value of 1.6% were slurried with 750 ml of toluene ata temperature of 20-25° C. for 4 days. The solid product was isolatedand dried under vacuum at a temperature of 45° C. The crystallineproduct obtained was characterized by PXRD confirming its structure(HPLC Purity: 99.8%, Yield: 86%).

Examples 2-7 Form IV of Ivabradine Hydrochloride

Examples 2 to 7 were carried out according to the process described inExample 1. In all cases the obtention of Form IV was confirmed by PXRD.

Example ivabradine HCl (g) Solvent (mL) Yield (%) 2 0.5toluene/acetone(10:1) 91 (25) 3 0.5 toluene/ethyl acetate 87 (10:1) (25)4 0.5 ethyl acetate/ethanol 70 (9:1) (5) 5 0.5 isopropyl acetate (25) 966 0.5 toluene (5) 88 7 0.5 toluene/ethanol (9:1) (5) 64

Example 8 Form IV of Ivabradine Hydrochloride

15.0 g of ivabradine hydrochloride were slurried with 750 ml of tolueneat T: 20-25° C. for 1 day. The solid product was isolated and driedunder vacuum at a temperature of 45° C. The crystalline product obtainedwas characterized by PXRD confirming its structure (Yield: 85%).

Example 9 Form IV of Ivabradine Hydrochloride

0.5 g of ivabradine hydrochloride were stirred with 25 ml of ethylacetate at a temperature of 20-25° C. After seeding with the productobtained in the Example 1 the suspension was slurried for 4 days. Thesolid product was isolated and dried under vacuum at a temperature of45° C. The crystalline product obtained was characterized by PXRDconfirming its structure (Yield: 88%).

Examples 10-20 Form IV of Ivabradine Hydrochloride

Ivabradine HCl, prepared according to its preparative example, wassuspended in the solvent at room temperature. The suspension wasslurried at a temperature of 20-25° C. The solid was filtered, driedunder vacuum and analysed by PXRD.

Weight Slurry Result Example Polymorph (mg) Solvent (mL) (days) PXRD 10Form α 10.0 MiBK (1.5) 3 Form IV 11 Form α 10.5 MiBK (1.5) 2 Form IV 12Form α 10.6 toluene (1.5) 2 Form IV 13 Form α + δd 10.5 MEK (1.5) 2 FormIV 14 Form δ 21.5 heptane (1.0) 4 Form IV 15 Form δ 20.6 MiBK (1.0) 4Form IV 16 Form δ 20.0 toluene (1.0) 4 Form IV 17 Form δ 20.4ethanol/ethyl 4 Form IV acetate (1:9) (1.0) 18 Form δ 20.5 ethanol/ 4Form IV n-pentane (1:9) (1.0) 19 Form δd 20.1 toluene (1.0) 4 Form IV 20Form δ + δd 20.2 toluene (1.0) 4 Form IV

Example 21 Form IV of Ivabradine Hydrochloride

11.2 mg of ivabradine HCl Form α and 10.0 mg of the Form IV preparedaccording to Example 1 were suspended in MiBK at room temperature. Thesuspension was slurried for 3 days at a temperature of 20-25° C. Thesolid was filtered, dried under vacuum. Analysis by PXRD confirmed thatthe crystalline ivabradine hydrochloride isolated was in its newcrystalline form.

Examples 22-24 Form IV of Ivabradine Hydrochloride

Examples 22 to 24 were carried out according to the process described inExample 21, In all cases the obtention of the novel crystalline form wasconfirmed by PXRD.

Form α Slurry Result Example (mg) Form IV (mg) Solvent (mL) (days) PXRD22 10.6 10.5 MiBK (1.5) 2 Form IV 23 10.0 10.6 toluene (1.5) 2 Form IV24 11.0 10.5 MEK (1.5) 2 Form IV

Example 25 Form IV of Ivabradine Hydrochloride

A solution which comprised 6.9 g of ivabradine in 90 mL of toluene wasstirred maintaining the temperature below about 40° C. 16 ml of achlorhydric acid solution in ethanol 1.75M were added. The solution wasseeded with the product obtained in the Example 1. Crystal growth waspromoted by stirring for 20 hours maintaining the temperature belowabout 40° C. The solid product obtained was isolated and dried undervacuum at a temperature of 65° C.

The crystalline product obtained was characterized by PXRD confirmingits structure (HPLC Purity: 99.17%, Yield: 68%).

Example 26 Tablets of Form IV of Ivabradine Hydrochloride

Tablets of ivabradine hydrochloride Form IV were prepared using theingredients listed in the following Table.

Components % Ivabradine hydrochloride 5.39 Maize starch 15.00Maltodextrin 5.00 Silica colloidal anhydrous 1.00 Monohydrate lactose73.11 Magnesium stearate 0.50

All the components, with the exception of magnesium stearate and silicacolloidal anhydrous, were mixed. Finally, silica colloidal anhydrous andmagnesium stearate were added and mixed. The blend was compressed in anexcentric tabletting machine.

The absence of any transformation of the crystalline Form IV ofivabradine hydrochloride was confirmed.

Example 27 Film-Coated Tablets of Form IV of Ivabradine Hydrochloride

Tablets were made with the indicated proportions of the ingredientsmention in the following Table.

Components % Ivabradine hydrochloride 5.39 Maize starch 10.00Maltodextrin 10.00 Silica colloidal anhydrous 1.00 Monohydrate lactose72.61 Magnesium stearate 1.00 Ethanol anhydrous* — Coating excipient3.00 *Ethanol evaporates during the drying process

All the components with the exception of magnesium stearate and silicacolloidal anhydrous were mixed and granulated using ethanol as agranulating solvent. Then a wet calibration of the granules wasperformed. The obtained granules were dried followed by a drycalibration of the granules. Thereafter, silica colloidal anhydrous andmagnesium stearate were added and mixed. The lubricated granulate wascompressed in an eccentric tabletting machine.

Finally, tablets were coated using conventional coating agents until aweight increase of approximately 3%.

The absence of any transformation of the crystalline Form IV ofivabradine hydrochloride was confirmed.

The invention claimed is:
 1. A process for preparing ivabradinehydrochloride Form IV with a powder X-ray diffraction comprising thefollowing degrees 2 theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and24.29, wherein the X-ray diffraction is measured using a CuKα radiation,the process comprising: a) slurrying ivabradine hydrochloride in asolvent system comprising toluene, ethanol, acetone, methyl ethylketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate andmixtures thereof; wherein said step of slurrying ivabradine occurs at atemperature of lower than 60° C. and the reaction time for said step ofslurrying ivabradine is less than 48 h; and b) isolating the ivabradinehydrochloride Form IV.
 2. The process of claim 1, wherein the step ofslurrying ivabradine occurs at a temperature between 10° C. to 30° C. 3.The process of claim 1, wherein the proportion in step (a) of liter ofthe solvent system versus kilogram of ivabradine hydrochloride Form IVis from 5 to
 50. 4. The process of claim 1, further comprising the stepof: c) drying the isolated ivabradine hydrochloride Form IV under vacuumpressure and at a temperature between 45° C. and 70° C.
 5. The processof claim 1, wherein the solvent system is chosen from toluene and ethylacetate.
 6. The process of claim 1, wherein the process results in ayield % of ivabradine hydrochloride Form IV that is greater than orequal to 64%.
 7. A process for preparing ivabradine hydrochloride FormIV with a powder X-ray diffraction comprising the following degrees 2theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein theX-ray diffraction is measured using a CuKα radiation, the processcomprising: i) stirring a solution of ivabradine free base in a solventsystem, wherein the solvent system comprises toluene, ethanol, acetone,methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropylacetate and mixtures thereof; ii) maintaining the solution at atemperature lower than 60° C.; iii) adding a solution of hydrochloricacid to obtain ivabradine hydrochloride; iv) seeding with the ivabradinehydrochloride Form IV; v) isolating the ivabradine hydrochloride Form IVand vi) drying the isolated ivabradine hydrochloride Form IV undervacuum pressure and at a temperature between 45° C. and 70° C.
 8. Aprocess for manufacturing a tablet of ivabradine hydrochloride Form IVwith a powder X-ray diffraction comprising the following degrees 2 theta(±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein the X-raydiffraction is measured using a CuKα radiation, the process comprising:a) slurrying ivabradine hydrochloride in a solvent system comprisingtoluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone,ethyl acetate, isopropyl acetate and mixtures thereof, and isolatingivabradine hydrochloride Form IV, according to the method of claim 1; b)drying the isolated ivabradine hydrochloride Form IV under vacuumpressure and at a temperature between 45° C. and 70° C.; c) mixing maizestarch, maltodextrin, and monohydrate lactose with ivabradinehydrochloride Form IV; d) adding magnesium stearate and anhydrouscolloidal silica to the mixture of step d); and e) compressing themixture of step e) in a tableting machine to form one or more tablets ofivabradine hydrochloride Form IV.
 9. The process of claim 8, furthercomprising coating the one or more tablets of ivabradine hydrochlorideForm IV using a coating excipient.
 10. The process of claim 9, whereinthe coating excipient is selected from a group consisting of derivativesof cellulose, more preferably hydroxypropylmethylcellulose (HPMC) andhydroxypropylcellulose (HPC), derivatives of Poly(methyl methacrylate)(PMMA), more preferably Eudragit®, Polyvinyl alcohol (PVA) and derivatesof Polyvinyl alcohol.
 11. A method for the treatment of chronic stableangina pectoris in an adult with normal sinus rhythm, the methodcomprising administering an effective amount of ivabradine hydrochlorideForm IV with a powder X-ray diffraction comprising the following degrees2 theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein theX-ray diffraction is measured using a CuKα radiation.
 12. The method ofclaim 11, further comprising administering at least a pharmaceuticallyacceptable excipient with said effective amount of ivabradinehydrochloride Form IV to said adult.
 13. The method of claim 11, whereinthe effective amount of ivabradine hydrochloride Form IV is administeredvia a tablet.
 14. The method of claim 13, wherein the tablet includes 5mg to 9 mg ivabradine hydrochloride Form IV.
 15. The method of claim 13,wherein the tablet is administered via oral administration.
 16. A methodfor the treatment of chronic stable angina pectoris in coronary arterydisease adults with normal sinus rhythm comprising administering to saidadult an effective amount of ivabradine hydrochloride Form IV with apowder X-ray diffraction comprising the following degrees 2 theta (±0.2)peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein the X-raydiffraction is measured using a CuKα radiation.
 17. The method of claim16, further comprising administering at least a pharmaceuticallyacceptable excipient with said effective amount of ivabradinehydrochloride Form IV to said adult.